Aliases: HOCT1, oct1_cds
Gene name: Solute carrier family 22 member 1 (SLC22A1)
OCT1 is primarily a hepatic uptake transporter, expressed on the sinusoidal membrane (blood side) of hepatocytes. It plays a key role in the disposition and hepatic clearance of mostly cationic drugs and endogenous compounds. It functions in conjunction with MATE1 that facilitates the biliary elimination of OCT1 substrates transported into the liver. Metformin is an important clinical substrate. Genetic polymorphisms of OCT1 are associated with altered metformin pharmacokinetics, safety, and efficacy, but the contributions of other cation transporters and their functional SNPs are also important.
Since the discovery of MATEs, DDIs ascribed to OCTs are being re-evaluated, and it is likely that some interactions may be re-assigned to MATEs. Regardless of this, the role of OCT1 as the first step in active hepatic extraction of cationic drugs remains important.
Current FDA and EMA guidances do not specifically recommend evaluation of OCT1 liabilities, although investigation of OCT2 or OCTs in general is advised. It is appropriate to consider evaluating OCT1 interactions for drugs that are likely to be co-administered with OCT/MATE substrates, particularly metformin. Although there is no guidance for MATEs either, simultaneous evaluation of their interactions is also advisable.
OCT1 is primarily expressed on the sinusoidal (blood side) membrane of hepatocytes. OCT1 is also located on the basolateral membrane of small intestinal enterocytes, renal proximal tubular cells, and with much lower abundance in some neurons, the heart, skeletal muscle, lung, tumor cells, and basophilic granulocytes [1, 2]. There are significant differences in relative tissue expression (notably in the liver and kidney) between rodents and humans, as well as inter-individual differences in humans [1, 2, 6].
Function, physiology, and clinically significant polymorphisms
OCT1 is a polyspecific, bi-directional, facilitative diffusional transporter with 12 predicted membrane spanning domains, and is predominantly expressed on the blood side (basolateral membrane) of hepatocytes. Although bi-directional, it typically behaves as an uptake transporter in vivo, extracting substrates from the blood into the hepatocyte, as the first step in the hepatic elimination of its drug substrates. OCT1 mediates Na+-independent transport of Type I organic cations (protonated molecules), such as tetraethylammonium (TEA), 1-methyl-4-phenylpyridinium (MPP+), N1-methylnicotinamide (NMN), dopamine, and choline , as well as Type II cations (larger and bulkier molecules) such as methyl-quinine and quinidine. OCT1-mediated organic cation transport is electrogenic and sensitive to membrane potential. The inhibitors of OCT1 with the highest in vitro affinity are atropine (IC50 1.2 µM) and prazosin (IC50 1.8 µM) [2, 4]. A large number of drugs have been identified as substrates or inhibitors of OCT1. A key drug substrate of OCT1 is the oral antidiabetic drug metformin, which must be transported into the hepatocyte (and adipose cells) to exert its pharmacological effect. OCT1 shares many substrates and inhibitors with the kidney-specific OCT2, the ubiquitously expressed OCT3, as well as with OCTNs and members of the MATE family of transporters. This cross-specificity is important. Firstly, MATE1 in the liver provides the final step in the elimination of drugs from the hepatocyte into the bile, thus complementing OCT1 uptake from the blood. Secondly, as being primarily renal, OCT2 provides an alternative systemic clearance mechanism. The roles of OCT3 and OCTNs are, however, more difficult to quantify.
Although there are significant differences in cation transporter expression between rodents and humans, carefully designed studies have helped to clarify some important roles of OCT1. In Oct1-/- mice, TEA accumulation in the liver was reduced relative to wild-type mice and Oct2-/-, indicating that Oct1 is the main sinusoidal uptake system for TEA . Small intestinal excretion of TEA was reduced by half, demonstrating that Oct1 mediates the basolateral uptake of TEA into enterocytes . Upon knocking out Oct1 from the mouse liver, elimination of Oct1 substrate drugs is shifted from the liver to the kidneys, increasing renal excretion of drugs .
The tyrosine kinase inhibitors (TKI) imatinib, nilotinib, gefitinib, and erlotinib exert selective and potent inhibitory effects on OCT1 in vitro. There are clinically relevant polymorphisms of OCT1 which are associated with increased metformin exposure, since OCT1 plays an important role in metformin transport into hepatocytes . Reduced expression is associated with non-synonymous coding variants of OCT1 such as rs12208357 . The OCT1 polymorphism M420del is associated with increased sensitivity to inhibition by erlotinib, suggesting the potential of clinical transporter-mediated DDIs between specific TKIs and OCT1, which may affect the disposition, efficacy, and toxicity of metformin and other drugs that are OCT1 substrates .
OCT1 is transcriptionally activated by PXR, PPARα, and HNF1α [9, 10].
Given the strong association of substrates and inhibitors of OCTs with MATEs, and the significant gap between the discovery of OCTs (1995) and MATEs (2005), DDIs previously ascribed to OCT1 are under re-evaluation. This has resulted in an enormous revival of interest in OCT-mediated DDI mechanisms generally. However, even where DDIs may be primarily re-assigned to MATEs, the role of OCT1 as the first step in active hepatic elimination remains important.
Biguanides (e.g., the OCT1 substrates metformin and phenformin), widely used as oral hypoglycemic agents for the treatment of type II diabetes mellitus, can produce lactic acidosis, a lethal, but rare side effect. OCT1 transports metformin into hepatocytes, and functional loss of variants of the OCT1 transporter is linked to the reduced hepatic uptake of metformin and subsequently, its pharmacodynamic effect by reducing oral glucose tolerance . Individuals carrying reduced function OCT1 alleles including SNPs in positions 420, 401 and 465, appear to have reduced metformin clearance based on the observed higher AUC and Cmax . Phenformin was withdrawn from the market due to altered pharmacokinetics resulting in lactic acidosis.
For several drugs which inhibit OCTs but are not OCT substrates, a higher affinity to OCT1 was observed compared to OCT2 or OCT3 e.g. the glutamate receptor antagonist phencyclidine, the antagonists of histamine receptors diphenylhydramine and ranitidine, the antagonist of the muscarinic acetylcholine receptor atropine, and the antidepressant desipramine.
There is an enormous revival of interest in OCT-mediated DDI mechanisms since the discovery of MATEs, and their complementary role in cation elimination. At least some interactions previously ascribed to OCTs may be re-assigned to MATEs, in due course. Regardless, the role of OCTs as the first step in active elimination of cationic drugs remains important.
Current FDA and EMA guidances do not recommend specific evaluation of OCT1 liabilities, although investigation of OCT2 or OCTs in general is advised. It is appropriate to consider evaluating OCT1 interactions for drugs that are likely to be co-administered with OCT substrates, particularly metformin. Although there is no guidance for MATEs, simultaneous evaluation of their interactions is also advisable.
|Location||Endogenous substrates||In vitro substrates used experimentally||Substrate drugs||Inhibitors|
|liver: hepatocytes sinusoidal membrane,
Intestine: enterocytes apical membrane, neurons
|choline, acetylcholine, agmatine, monoamine neurotransmitters||tetraethylammonium (TEA),
N-methylphenylpyridinium (MPP+), tetrapropylammonium, tetrabutylammonium,
|quinine, quinidine, disopyramide, atropine, prazosin|
1. Jonker, J.W. and A.H. Schinkel, Pharmacological and physiological functions of the polyspecific organic cation transporters: OCT1, 2, and 3 (SLC22A1-3). J Pharmacol Exp Ther, 2004. 308(1): p. 2-9.
2. Koepsell, H., Polyspecific organic cation transporters: their functions and interactions with drugs. Trends Pharmacol Sci, 2004. 25(7): p. 375-81.
3. Koepsell, H., Organic cation transporters in intestine, kidney, liver, and brain. Annu Rev Physiol, 1998. 60: p. 243-66.
4. Koepsell, H. and H. Endou, The SLC22 drug transporter family. Pflugers Arch, 2004. 447(5): p. 666-76.
5. Jonker, J.W., et al., Deficiency in the organic cation transporters 1 and 2 (Oct1/Oct2 [Slc22a1/Slc22a2]) in mice abolishes renal secretion of organic cations. Mol Cell Biol, 2003. 23(21): p. 7902-8.
6. Jonker, J.W., et al., Reduced hepatic uptake and intestinal excretion of organic cations in mice with a targeted disruption of the organic cation transporter 1 (Oct1 [Slc22a1]) gene. Mol Cell Biol, 2001. 21(16): p. 5471-7.
7. Nies, A.T., et al., Expression of organic cation transporters OCT1 (SLC22A1) and OCT3 (SLC22A3) is affected by genetic factors and cholestasis in human liver. Hepatology, 2009. 50(4): p. 1227-40.
8. Minematsu, T. and K.M. Giacomini, Interactions of tyrosine kinase inhibitors with organic cation transporters and multidrug and toxic compound extrusion proteins. Mol Cancer Ther, 2011. 10(3): p. 531-9.
9. Saborowski, M., G.A. Kullak-Ublick, and J.J. Eloranta, The human organic cation transporter-1 gene is transactivated by hepatocyte nuclear factor-4alpha. J Pharmacol Exp Ther, 2006. 317(2): p. 778-85.
10. Tirona, R.G. and R.B. Kim, Nuclear receptors and drug disposition gene regulation. J Pharm Sci, 2005. 94(6): p. 1169-86.
11. Shu, Y., et al., Effect of genetic variation in the organic cation transporter 1, OCT1, on metformin pharmacokinetics. Clin Pharmacol Ther, 2008. 83(2): p. 273-80.